Drug dependence test 5

What is desensitization

decreased signaling/effector response

What is neuroadaptation to repeated drugs dependent on

region-specific and time-dependent

what is internalization

loss of receptors from cell surface

what is downregulation

loss of receptors due to degradation

What are the 5 components of g-protein signaling

1.binding of neurotransmitter or drug to receptor

2.activates the G-protein

3.which regulates a target protein

4.change in enzyme activity produces/activates the second messenger

5.second messenger targets include protein kinases that catalyze phosphorylation of target proteins, which regulates their function

what is the mechanism of g-protein coupled receptor signaling during tolerance

1.binding of drug to receptor during chronic use

2.desensitizes G-protein activation

3.which reduces regulation of downstream protein

4.desensitization reduces effect on enzyme activity, which alters second messenger signaling and effects on target proteins

what does GRK do?

G-protein coupled receptor kinase, phosphorylates agonist-activated GPCR to promote beta-arresting binding, which leads to desensitization

what do arrestins do ?

interfere with G-protein coupling of agonist-activated GPCR and promotes internalization

what is the mechanism of g-protein coupled receptor adaptation: desensitization and downregulation

agonist(drug) binds to GPCR

GPCR is phosphorylated by GRK

beta-arrestin binds to phosphorylated receptor

as a result of beta-arrestin binding, the receptor is blocked from activating G-proteins, and effects are not regulated (desensitization)

binding of arrestin also initiates internalization and alternate signaling pathways

What is GPCR recycling

Resensitization, acidity of the endosomal vesicle allows GPCR dephosphorylation and recycling to the membrane; receptor “recovers”

What is GPCR degradation

downregulation, the endosome fuses with lysosome and the receptor is degraded

How can GPCRs signal G-proteins

signal through effectors ( enzymes, ion channels)

How can GPCRs signal beta-arrestin

signaling via alternative pathways

What is the evidence that GRK and beta-arrestin regulated GPCR desensitization and tolerance

lac of olfactory desensitization and reduced opioid tolerance in GRK3 knockout mice. reduced tolerance to morphine and THC and region dependent reduction in MOR and CB1 desensitization in beta-arrestin 2 knockout mice

What is evidence that beta-arrestin also regulates acute drug effects

reduced morphine constipation and respiratory depression, enhance morphine antinociception and reward, enhanced cannabinoid antinocicpetion and hypothermia in beta-arrestin 2 knockout mice

How can tolerance and dependence be distinguished mechanistically

tolerances is reduced in beta-arrestin knockout mice but withdrawal is not affected

Why are biased ligands important

develop drugs that selectively promote signaling via desired pathway to enhance positive therapeutic effect and minimize negative side effects and desensitization/tolerance

What is the mechanism of GPCR adaptation in dependence

dependence is revealed during spontaneous (drug cessation) or antagonist-precipitated withdrawal. endogenous system adapts to the presence of drug to maintain homeostasis; when the drug is removed it disturbs the balance of the system and produces withdrawal signs

What is the adaptation of cAMP pathway to repeated drugs

1. chronic drug

2.increases level of adenyl cyclase

3.withdrawal of drug leads to increased cAMP, called cAMP overshoot

4.increased activity at second messenger targets including protein kinases and gene expression

5.causes changes in metabolic activity and gene expression

What is time dependent regulation of adenyl cyclase and cAMP

1.acute opioid; inhibits AC to reduce cAMP production

2.repeated opioid treatment: induction of AC and protein kinase leads to recovery of functional activity of the cAMP pathway, and tolerance/dependence

3.remove opioid: cAMP overshoot due to AC up regulation elicits withdrawal response

What is an effect of an upregulated cAMP pathway

contributes to the hyper excitability of NE neurons in locus coeruleus during opioid physical withdrawal

What is the functional consequence of cAMP up regulation on the locus coeruleus

physical dependence and withdrawal,

What is the functional consequence of cAMP up regulation on the nucleus accumbens

dysphoria during early withdrawal periods

How are transcription factors regulated in drug use

1.drugs bind to targets

2.intracellular signaling pathways are activated/inhibited

3.signaling proteins activate/inhibit transcription factors

4.transcription factors regulate target genes to enhance or reduce production of specific proteins

What is the role of CREB in drug abuse

CREB is increased in the nucleus accumbent by repeated administration of opioids, cocaine, amphetamine. increased CREB reduces reward for cocaine, opioids, sucrose BUT enhances reward for nicotine. also involved in depression, learning and memory

How does CREB regulate target genes

CREB increase dynorphin in the mesolimbic system. dynorphin binds to kappa opioid receptors, which inhibits dopamine release from the VTA neurons projecting to nucleus accumbent and is associated with dysphoria

What is dFosB

dFosB is a truncated splice variant of FosB that is stable and accumulates with repeated drug administration. it is increased in the nucleus accumbent by abused drugs and natural rewards. over expression of dFosB in NAc enhances rewarding effects of drugs.

How do opioids affect CREB and dFosB?

for certain drugs, time-specific expression is associated with dysphoria at earlier points (CREB) and sensitization at later points(dFosB)

What gene does dFosB target

targets dynorphin and causes a decrease in the nucleus accumbent and hippocampus brain region. has effects on reward, plasticity, and dendritic structure

What is the main difference between CREB and dFosB?

CREB decreases reward for opioids, physchostimulants; dFosB enhances reward

How do opioids affect the NAc, PFC, and VTA?

opioids decrease dendritic spine density and dendritic arborization in PFC, NAc, and VTA

How does dFosB affect dendritic spines in long term adaptations

dendritic spine number is increased after cocaine or expression of dFosB. This effect can be blocked by viral overexpression of G9a or dJUND(dFosB antagonist)

What are epigenetic modifications

heritable changes in gene expression.

What is the best described epigenetic mechanism for drugs of abuse

histone modifications that either activate or repress gene expression

How can chronic drugs affect epigenetic modifications

chronic drugs can produce epigenetic modifications so that subsequent drug challenge induces the gene to a greater (primed) or lesser (desensitized) extent

What are the dimensions of transition/change

psychosocial, cognitive, physical, legal, reproductive

What are social development characteristics of adolescence

movement away from family, peer orientation

What are physical development characteristics of adolescence

growth spurt, sexual maturity

What are risk perception characteristics of adolescence

risk perception decreases, causes increase in risk tasking

What are reward sensitivity characteristics of adolescence

sensation seeking increases, preference for novelty, decreased sensitivity to consequences, impulsivity

What are disorders with adolescent onset

schizophrenia, substance abuse, depression and bipolar disorder, anorexia nervosa and bulimia

Why might an adolescent use or abuse illicit drugs

escapism, recreation (pleasure seeking), peer pressure, addiction, availability, heredity, family history

How is brain composition in childhood

by age 6, brain is 95% of adult size. neuronal connections increase throughout childhood. the maturation process is not complete until age 24

What does the brain contain at birth?

at birth, brain contains mostly grey matter(neurons, cell bodies, and dendrites). minimal white matter (myelin): insulation for neurons = myelination. myelination increases efficiency of conduction

What brain construction occurs at age 11-12?

neurons get bushier and increase in the number of connections. at about age 11, this thickening undergoes pruning. at the same time, myelin sheaths that encase nerve cells thicken. myelin sheaths are like insulation on a wire; they make nerve cells transmissions faster and more efficient. net effect when complete is faster, yet fewer, connections in the brain

How does brain maturation differ in brain regions

back of brain matures before to the front of the brain. sensory and physical activities favored over complex, coginitive-demanding activities. propensity toward risky, impulsive behaviors. poor planning and judgement

What are characteristics of the back of the brain maturing before the front?

activities with high excitement and low effort preferred. poor modulation of emotions. heightened interest in novel stimuli

How do adults vs. teens read emotions

adults rely more on the frontal cortex while teens rely more on the amygdala

Why is the adolescent brain imbalanced? and what does it cause

emotional responses are heightened and cognitive controls are immature. leads to being developmentally primed to use drugs

What are “the big three” gateway drugs

alcohol, nicotine, and marijuana

Why are clinical studies on adolescent drug abuse challenging

legal/liability, ethical issues, clinical study dropout rate, varying intake patterns

Why are animal models of adolescence drug abuse helpful

brain development in juvenile rodents has been reported to display similar patterns to human beings

neuroanatomical studies describe massive synaptic pruning of DA receptors during adolescence in rodents

similar behavioral indicators as in adolescent humans: impulsivity, novelty seeking

How is adolescent intoxicity response compared to adolescent rats

adolescent rats are less sensitive to the sedative and motor impairment effects of intoxication: reduced sensitivity to intoxication in humans.

How are adolescents susceptible to nicotine dependence compared to adults?

adolescents are more susceptible to nicotine dependence than adults

Why are teens more at risk for drug abuse?

Teens have enhanced sensitivity to drug reward with reduced drug-induced aversive effects

What factors affect adolescent vulnerability

presence of a psychiatric disorder, physical abuse, poor social skills

What are adolescent individual-related risk factors

early age of onset, presence of early childhood behavioral problems, poor academic performance, risk-taking behavior, favorable beliefs, shorter attention spans, increased impulsivity and irritability

What are adolescent family-related risk factors

favorable beliefs in parents, parental tolerance of substance use, lack of closeness to parent, lack of discipline, parental substance use

What are adolescent peer-related risk factors

peer substance use, favorable peer attitudes to use, greater orientation of adolescents to peers as opposed to parent

What are adolescent community-related risk factors

low SE status, high population density, high crime rate

can addiction be prevented by delaying drug use onset

every year use of a substance is delayed, the risk of developing a substance use disorder is reduced

What is the placenta

a rich endocrine organ with the fetus as a parasite. Has two sides: maternal and fetal side. maternal side is a rough material composed of endometrial tissue. the fetal side is composed of the amniotic membrane.

What is the human chorionic gonadotropin hormone (hCG) for

implantation

what does the human placental lactogen (hPL) do

stimulate milk glands

why are estrogen and progesterone important

maintenance of pregnancy

How does blood flow and O2 levels change during pregnancy

A small fetus doesn’t need much O2 and less blood flow, as pregnancy continues fetus needs increase in blood flow and higher O2 levels

How does an abnormal pregnancy change the uterine wall and spinal artery

the cytotrohphoblasts and syncytiotrophoblasts aren’t able to invade the spinal artery

what are critical functions of the placenta

bringing nutrients and oxygen to the fetus, removing harmful waste, providing immune protection, producing hormones to support fetal development

What are maternal drug abuse/adverse effects

prematurity and low birth weight, stillbirth, infant mortality/failure to thrive, withdrawal symptoms after birth, neurosensory deficits

What are other risks from maternal drug abuse/adverse effects

infectious diseases, exposure to toxins, poor nourishment

What is growth retardation from fetal alcohol syndrome

low birth weight, short body, small head circumference. associated with alcohol intake during first 2 months

What is CNS abnormalities from fetal alcohol syndrome

microencephaly and brain damage, slow development, hyperactivity, seizures. associated with alcohol intake 1st trimester

What are dysmorphic characteristics from fetal alcohol syndrome

flat face and nose, thin upper lip, small chin, abnormally formed limbs. associated with alcohol intake during 1st trimester

What are the direct adverse nicotine effect on the fetus

blood flow restriction to the placenta due to the vasoconstrictive effects of catecholamines released following nAChrS activation

What are the indirect adverse nicotine effect on the fetus

poor nutritional status- anorexigenic effects. carbon monoxide exposure

What are symptoms of nicotine on the fetus

increased mortality 20-35%, intrauterine growth retardation, low birth weight with no change in head circumference, congenital abnormalities due to lack of oxygen, irritability, SIDS

what are long term effects of nicotine on a child

hyperkinetic(increased change of ADHD), respiratory problems, delayed learning abilities, behavioral problems

What are marijuana effects on the fetus

confounding effects due to poly-drug use, increased risk of miscarriage, low birth weight, premature delivery and developmental delays. increased carbon monoxide and carbon dioxide levels in blood lead to reduced oxygen delivery to fetus

What are marijuana effects on the newborn

withdrawal like symptoms, including excessive crying and poor sleep and trembling. difficulty with state regulation: ability to adjust to touch and environment.

What are opioid use effects on the mother

analgesic, antitussive, nausea and constipation, pin point pupils, respiratory depression, transmission of HIV/AIDS

What are opioid use effects on the fetus

small head circumference,

low birth weight,

severe and protracted withdrawal: treat with methadone and buprenorphine

respiratory depression

increased risk of SIDS

increased risk of infection (HIV and AIDS)

what are long term opioid effects on child’s growth and development

growth retardation, sleep disturbances, hyperactivity, learning disabilities/behavioral problems

what are the new opioid treatment guidelines

methadone maintenance therapy (full agonist)

Subutex: buprenorphine (partial agonist)

Suboxone:mixture of buprenorphine and naloxone(antagonist)

New threat: xylazine(depressant) in illicit opioids

What are kratom actions on the body

reduces pain, anxiety and depression. increases energy

what are kratom side effects

weight loss, nausea and vomiting, liver damage, changes in urination, and constipation

what are kratom overdose effects

dizziness, delusions and seizures, respiratory suppression leading to coma and death

What are kratom effects on the mother and newborn

Withdrawal: dependence from long term use. sweating, restlessness, and trembling.

newborn: excessive crying and poor sleep and trembling

treatment: methadone

How does cocaine affect a pregnancy

crosses the placenta, enters the fetal circulation, elimination from fetus slower than adult, early pregnancy use increases risk of miscarriage. late pregnancy use increase risk placental disruption

What are cocaine effects on the mother

decreased appetite, increased heart rate and blood pressure, increased body temperature and sweating, insomnia, muscle spasms. overdose: convulsions, cardiac arrhythmia

What is fetal distress from cocaine use

blood vessels constrict depriving fetus of oxygen nutrients

heart rate rises leading to heart attack and withdrawal signs just as the adult

withdrawal is more severe and prolonged (brain damage)

low birth rate, small head circumference

What are METH effects on the mother

preeclampsia, premature delivery and placental abruption

What are meth effects on the baby

low birth weight, intrauterine growth restriction, increased incidence of poor cardio respiratory adaptation, cardiac defects and a floppy muscle tone

what are long term meth effects on a child

increased emotional reactivity and anxiety/depression, socially withdrawn, attention and cognitive problems that could lead to poorer academic outcomes

what are effects of prescription stimulant medications on a pregnancy

preterm birth and low birth weight

withdrawal symptoms

persistent pulmonary hypertension and heart defects

birth defects: brain damage and limb malformations

what are effects of prescription antidepressants on a pregnancy

association with autism

withdrawal symptoms in newborns

breathing problems

What does lithium (mood stabilizer) do to a fetus

associated with congenital cardiac abnormalities, learning deficits in addition to neurotoxicity and withdrawal syndrome

what does valproate (mood stabilizer ) do to a fetus

causes neural tube and cardiac defects

what does carbamazepine do to a fetus

major teratogen leading to neural tube defects and other birth defects, low birth weight, vitamin K deficiency

what does lamotrigine (mood stabilizer) do to a fetus

less severe birth defects

What does nicotine have an effect on in prenatal drug exposure

fetal growth, neurobehavioral, long term behavior, cognition, language , achievement